Anesthetic Compounds

ABSTRACT

In one embodiment the invention provides novel compounds of Formula (I) as well as prodrugs, salts, hydrates, solvates and N-oxides thereof. The invention also provides pharmaceutical compositions that include such compounds as well as methods for making and methods for using such compounds in medical therapy.

This application claims priority to U.S. Provisional Application Nos.60/832,174, filed 19 Jul. 2006; 60/832,694, filed 20 Jul. 2006; and60/837,697, filed 14 Aug. 2006.

Local anesthetics produce loss of sensation by binding to sodiumchannels and inhibiting sodium currents which causes blockade of sodiumchannel dependent impulse conduction. The action of local anesthetics isreversible at clinically relevant concentrations thus allowing forcomplete recovery of nerve and muscle function without damage to nervefibers or cells.

Many clinically useful local anesthetics are comprised of a substitutedaromatic group attached to a carboxylic acid derivative such as an amideor ester to which is connected a secondary or tertiary amino group viaan alkyl linker. Ester anesthetics, whose clinical use was firstdiscovered at the beginning of the 20^(th) century include, for example,cocaine, procaine, tetracaine, benzocaine, amethocaine andchloroprocaine. Amide anesthetics, which were first clinically usedprior to the Second World War include, for example, lidocaine,prilocaine, mepivacaine, ropivacaine, etidocaine, levobupivacaine andbupivacaine. Despite being discovered first, the use of esteranesthetics has been largely supplanted by amide anesthetics.

Notwithstanding the chemical similarities between these two classes oflocal anesthetics, clinically important differences exist between amideand ester anesthetics. Significantly all local anesthetics share similartoxicity profiles (e.g., seizures from central nervous system toxicity,arrhythmia and death from cardiac toxicity) which suggests that the rateof metabolism may be an important factor in fatalities caused byanesthetics. Ester anesthetics are rapidly hydrolyzed in vivo by plasmacholinesterases while amide anesthetics are hydrolyzed much less rapidlyby hepatic proteases. Rapid metabolism prevents esters from reachingtoxic level in vivo even with large or repeated doses. Amideanesthetics, in contrast, can accumulate to toxic levels with large orrepeated dosages because of slow hydrolysis in vivo.

Another important issue with currently used local anesthetics is thelimited duration of action which is often too short to relievepost-operative pain, slow onset of action which limits utility inpostoperative settings in addition to aforementioned safety issues.Further, many currently used anesthetics cause pain and discomfort whenadministered to a patient.

Accordingly, in view of the foregoing, what is needed are localanesthetics which have rapid onset, longer duration of action, and/orminimal side effects.

The present invention satisfies these and other needs by providing novelester local anesthetics. Also disclosed herein are methods of makingnovel ester local anesthetics, pharmaceutical compositions of novelester local anesthetics and methods of using novel ester localanesthetics and pharmaceutical compositions thereof to induce and/ormaintain anesthesia and/or analgesia.

In one embodiment the invention provides a compound of the inventionthat is of structural Formula (I):

or a prodrug, salt, hydrate, solvate or N-oxide thereof wherein:

each R¹ is independently hydrogen, —F, —Cl, —Br, —I, —R⁶, —OR⁶, —SR⁶,—NR⁶R⁷ or —C(O)NR⁶R⁷,—provided that at least one R¹ is R⁶, —OR⁶, —SR⁶,—NR⁶R⁷ or —C(O)NR⁶R;

p is an integer from 1 to 3;

X is —O— or —S—;

R² and R³ are independently hydrogen or (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups oroptionally one of either R² or R³ and one of either R⁴ or R⁵ togetherwith the atoms to which they are bonded form a cycloheteroalkyl ring; orR² is the sidechain of an amino acid and R³ is H;

n is 1, 2, 3, or 4;

R⁴ and R⁵ are independently H, (C1-C6) alkyl optionally substituted withone or more of the same or different R⁸ groups or optionally R⁴ and R⁵together with the nitrogen atom to which they are bonded form acycloheteroalkyl ring that is optionally substituted with one or more(C1-C6) alkyl;

R⁶ and R⁷ are independently hydrogen, alkyl optionally substituted withone or more of the same or different R⁸ groups, cycloalkyl optionallysubstituted with one or more of the same or different R⁸ groups,cycloheteroalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, aryl optionally substituted with one or more of thesame or different R⁸ groups or heteroaryl optionally substituted withone or more of the same or different R⁸ groups; or optionally R⁶ and R⁷together with the nitrogen atom to which they are bonded form acycloheteroalkyl ring and

R⁸ is —F, —Cl, —Br, —I, —R⁶, —OR⁶, —SR⁶, —NR⁶R⁷, —CF₃, —CN, —C(O)R⁶,—C(O)OR⁶, —C(O)SR⁶, —C(O)NR⁶R⁷, or aryl which is optionally substitutedwith one or more —F, —Cl, —Br, —I, —R⁶, —OR⁶, —SR⁶, —NR⁶R⁷, —CF₃, —CN,—C(O)R⁶, —C(O)OR⁶, —C(O)SR⁶, or —C(O)NR⁶R⁷.

In one embodiment the compounds of formula I exclude the followingstructures:

In another embodiment the invention provides a method for inducingand/or maintaining anesthesia and/or analgesia comprising administeringto a patient in need of such treatment or prevention a therapeuticallyeffective amount of a compound of formula (I) or a prodrug, salt,hydrate, solvate or N-oxide thereof.

In another embodiment the invention provides a pharmaceuticalcomposition comprising a compound of formula (I) or a prodrug, salt,hydrate, solvate or N-oxide thereof, and a pharmaceutically acceptablevehicle.

In another embodiment the invention provides a method of inducing ormaintaining local anesthesia in a patient comprising administering tothe patient a compound of formula (I) or a prodrug, salt, hydrate,solvate or N-oxide thereof.

In another embodiment the invention provides a method of treating orpreventing pain in a patient comprising administering to the patient inneed thereof a compound of formula (I) or a prodrug, salt, hydrate,solvate or N-oxide thereof.

In another embodiment the invention provides a compound of formula I, ora prodrug, salt, hydrate, solvate or N-oxide thereof for use in medicaltherapy.

In another embodiment the invention provides the use of a compound offormula I, or a prodrug, salt, hydrate, solvate or N-oxide thereof toprepare a medicament for inducing or maintaining local anesthesia in amammal such as a human.

In another embodiment the invention provides the use of a compound offormula I, or a prodrug, salt, hydrate, solvate or N-oxide thereof toprepare a medicament for treating or preventing pain in a mammal such asa human.

The invention also provides novel processes and synthetic intermediatesdisclosed herein that are useful for preparing a compound of formula I,or a prodrug, salt, hydrate, solvate or N-oxide thereof. Some compoundsof formula I may be useful as intermediates for preparing othercompounds of formula I.

DETAILED DESCRIPTION Definitions

“Alkyl” by itself or as part of another substituent refers to asaturated or unsaturated, branched, straight-chain or cyclic monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene or alkyne. Typical alkylgroups include, but are not limited to, methyl; ethyls such as ethanyl,ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl,cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. In some embodiments, an alkyl groupcomprises from 1 to 20 carbon atoms. In other embodiments, an alkylgroup comprises from 1 to 10 carbon atoms. In still other embodiments,an alkyl group comprises from 1 to 6 carbon atoms.

“Alkanyl” by itself or as part of another substituent refers to asaturated branched, straight-chain or cyclic alkyl radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkene. The groupmay be in either the cis or trans conformation about the double bond(s).Typical alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl;butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Typicalalkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Alkoxy” by itself or as part of another substituent refers to a radical—OR³¹ where R³¹ represents an alkyl or cycloalkyl group as definedherein. Representative examples include, but are not limited to,methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

“Amino Acid,” refers to the natural amino acids (e.g. Ala, Arg, Asn,Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu, Lys, Met, Phe, Pro,Ser, Thr, Trp, Tyr, and Val) in D or L form, as well as unnatural aminoacids (e.g. phosphoserine, phosphothreonine, phosphotyrosine,hydroxyproline, gamma-carboxyglutamate; hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, citruline, α-methyl-alanine, para-benzoylphenylalanine,phenylglycine, propargylglycine, sarcosine, and tert-butylglycine).

“Compounds” as used herein refers to compounds encompassed by structuralFormula (I) and disclosed herein and includes any specific compoundswithin this formula whose structure is disclosed herein. Compounds maybe identified either by their chemical structure and/or chemical name.The compounds described herein may contain one or more chiral centersand/or double bonds and therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers. Accordingly, all possible enantiomers and stereoisomersof the compounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures are included in thedescription of the compounds herein. Enantiomeric and stereoisomericmixtures can be resolved into their component enantiomers orstereoisomers using separation techniques or chiral synthesis techniqueswell known to the skilled artisan. The compounds may also exist inseveral tautomeric forms including the enol form, the keto form andmixtures thereof. Accordingly, the chemical structures depicted hereinencompass all possible tautomeric forms of the illustrated compounds.

“Aryl” as used herein refers to a phenyl radical or an ortho-fusedbicyclic carbocyclic radical having about nine to ten ring atoms inwhich at least one ring is aromatic. Examples of aryl include phenyl,indenyl, and naphthyl.

“Heteroaryl” as used herein refers to a radical of a monocyclic aromaticring containing five or six ring atoms consisting of carbon and one tofour heteroatoms each selected from the group consisting of non-peroxideoxygen, sulfur, and N(X) wherein X is absent or is H, O, (C₁-C₄)alkyl,phenyl or benzyl, as well as a radical of an ortho-fused bicyclicheterocycle of about eight to ten ring atoms derived therefrom,particularly a benz-derivative or one derived by fusing a propylene,trimethylene, or tetramethylene diradical thereto. Examples ofheteroaryl include furyl, imidazolyl, triazolyl, triazinyl, oxazoyl,isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl,tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or itsN-oxide), indolyl, isoquinolyl (or its N-oxide) and quinolyl (or itsN-oxide).

“Cycloalkyl” as used herein refers to a cyclic “alkyl” group.

The compounds described also include isotopically labeled compoundswhere one or more atoms have an atomic mass different from the atomicmass conventionally found in nature. Examples of isotopes that may beincorporated into the compounds disclosed herein include, but are notlimited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc.

Compounds may exist in unsolvated forms as well as solvated forms,including hydrated forms. Certain compounds may exist in multiplecrystalline or amorphous forms. In general, all physical forms arewithin the scope of the present disclosure.

“Cycloheteroalkyl” by itself or as part of another substituent, refersto a saturated or unsaturated cyclic alkyl radical in which one or morecarbon atoms (and any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatom. Typical heteroatoms toreplace the carbon atom(s) include, but are not limited to, N, P, O, S,Si, etc. Where a specific level of saturation is intended, thenomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.Typical cycloheteroalkyl groups include, but are not limited to, groupsderived from epoxides, azirines, thiiranes, imidazolidine, morpholine,piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine and thelike.

“Pharmaceutical composition” refers to at least one compound and apharmaceutically acceptable vehicle.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include: (1) acid addition salts, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound is administered.

“Patient” includes mammals, such as humans. The terms “human” and“patient” are used interchangeably herein.

“Protecting group” refers to a grouping of atoms that when attached to areactive functional group in a molecule masks, reduces or preventsreactivity of the functional group. Examples of protecting groups can befound in Green et al., “Protective Groups in Organic Chemistry,” (Wiley,2^(nd) ed. 1991) and Harrison et al., “Compendium of Synthetic OrganicMethods,” Vols. 1-8 (John Wiley and Sons, 1971-1996). Representativeamino protecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“SES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for inducing and/or maintaininganesthesia or for providing analgesia, is sufficient to effect suchinduction or maintenance of anesthesia and/or analgesia. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity, and the age, weight, etc., of the patientto be treated.

Reference will now be made in detail to various embodiments. It will beunderstood that the invention is not limited to these embodiments. Tothe contrary, it is intended to cover alternatives, modifications, andequivalents as may be included within the spirit and scope of theallowed claims.

In one embodiment a compound of structural Formula (I) is provided:

or prodrugs, salts, hydrates, solvates or N-oxides thereof wherein:

each R¹ is independently hydrogen, —F, —Cl, —Br, —I, —R⁶, —OR⁶, —SR⁶,—NR⁶R⁷ or —C(O)NR⁶R⁷,—provided that at least one R¹ is R⁶, —OR⁶, —SR⁶,—NR⁶R⁷ or —C(O)NR⁶R;

p is an integer from 1 to 3;

X is —O— or —S—;

R² and R³ are independently hydrogen or (C1-C6) alkyl optionallysubstituted with one or more of the same or different R⁸ groups oroptionally one of either R² or R³ and one of either R⁴ or R⁵ togetherwith the atoms to which they are bonded form a cycloheteroalkyl ring;

n is an integer from 0 to 4;

R⁴ and R⁵ are independently (C1-C6) alkyl optionally substituted withone or more of the same or different R⁸ groups or optionally R⁴ and R⁵together with the nitrogen atom to which they are bonded form acycloheteroalkyl ring;

R⁶ and R⁷ are independently hydrogen, alkyl optionally substituted withone or more of the same or different R⁸ groups, cycloalkyl optionallysubstituted with one or more of the same or different R⁸ groups,cycloheteroalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, aryl optionally substituted with one or more of thesame or different R⁸ groups or heteroaryl optionally substituted withone or more of the same or different R⁸ groups; and

R⁸ is —F, —Cl, —Br, —I, —R⁶, —OR⁶, —SR⁶, —NR⁶R⁷, —CF₃, —CN, —C(O)R⁶,—C(O)OR⁶, —C(O)SR⁶ or —C(O)NR⁶R⁷.

In some embodiments, R⁴ and R⁵ form only one cycloheteroalkyl ring. Inother embodiments, R¹ is hydrogen, —Cl, —R⁶, —OR⁶ or —NR⁶R⁷, R² and R³are hydrogen or (C1-C6) alkyl and R⁴ and R⁵ are (C1-C6) alkyl. In stillother embodiments, R¹ is hydrogen, —Cl, —R⁶, —OR⁶ or —NR⁶R⁷. In stillother embodiments, R² and R³ are hydrogen or (C1-C6) alkyl. In stillother embodiments, R⁴ and R⁵ are (C1-C6) alkyl. In still otherembodiments, R⁸ is —F, —Cl, —R⁶, —OR⁶, —SR⁶, —NR⁶R⁷, —C(O)R⁶, —C(O)OR⁶or —C(O)NR⁶R⁷.

In some embodiments, p is 2, R¹ is —Cl and —NH₂, X is O, n is 2, R² andR³ are hydrogen, and R⁴ and R⁵ together with the nitrogen atom to whichthey are bonded form a cycloheteroalkyl ring. In other embodiments, acompound having the structure below is provided:

In some embodiments, p is 2, R¹ is —Cl and —NH₂, X is O, n is 2, each R³is hydrogen, R² is hydrogen and R² and R⁴ together with the atoms towhich they are bonded form a cycloheteroalkyl ring and R⁵ is hydrogen or(C1-C6) alkyl. In other embodiments compounds having the structuresbelow are provided:

In other embodiments, compounds having the structures below areprovided:

In still other embodiments, compounds having the structures below areprovided:

In some embodiments, p is 2, R¹ is —Cl and —NH₂, X is O, n is 3, R³ ishydrogen, R² is hydrogen and R² and R⁴ together with the atoms to whichthey are bonded form a cycloheteroalkyl ring and R⁵ is hydrogen or(C1-C6) alkyl. In still other embodiments, compounds having thestructures below are provided:

In some embodiments, p is 2, R¹ is —Cl and —NH₂, X is O, n is 4, R³ ishydrogen, R² is hydrogen and one R² and R⁴ together with the atoms towhich they are bonded form a cycloheteroalkyl ring and R⁵ is hydrogen or(C1-C6) alkyl. In other embodiments, compounds having the structuresbelow are provided:

In some embodiments, p is 2, R¹ is OR⁶ and —NH₂, X is O, n is 2, R² andR³ are hydrogen and R⁵ is (C1-C6) alkyl. In other embodiments, acompound having the structure below is provided:

In some embodiments, p is 3, each R¹ is (C1-C6) alkyl, X is O, n is 2,R² and R³ are hydrogen and R⁵ is (C1-C6) alkyl. In other embodiments, acompound having the structure below is provided:

In some embodiments, R¹ is (C1-C6) alkyl, OR⁶ or —NH₂, X is S, n is 2,R² and R³ are hydrogen and R⁵ is (C1-C6) alkyl. In other embodiments, acompound having the structure below is provided:

In some embodiments, R¹ is (C1-C6) alkyl, OR⁶ or —NH₂, X is O, n is 3,R² and R³ are hydrogen and R⁵ is (C1-C6) alkyl. In other embodiments, acompound having the structure below is provided:

In some embodiments, R¹ is (C1-C6) alkyl, OR⁶ or —NH₂, X is O, n is 2,R² is hydrogen, R³ is hydrogen or (C1-C6) alkyl and R⁴ and R⁵ are(C1-C6) alkyl. In other embodiments, compounds having the followingstructures below are provided:

In some embodiments, R¹ is (C1-C6) alkyl, OR⁶ or —NH₂, X is O, n is 2,R² and R³ are hydrogen. In other embodiments, compounds having thestructures below are provided:

In some embodiments, R¹ is (C1-C6) alkyl, OR⁶ or —NH₂, X is O, n is 2,R² is hydrogen, R³ is hydrogen or (C1-C6) alkyl and R⁴ and R⁵ are(C1-C6) alkyl. In other embodiments, compounds having the structurebelow are provided:

In another embodiment the invention provides a compound of formula II:

or a prodrug, salt, hydrate, solvate or N-oxide thereof, wherein:

Z is a group of the following formula:

each R¹ is independently hydrogen, —F, —Cl, —Br, —I, —R⁶, —OR⁶, —SR⁶,—NR⁶R⁷ or —C(O)NR⁶R⁷;

p is an integer from 1 to 3;

X is —O— or —S—;

R² is the sidechain of an amino acid;

R⁴ and R⁵ are independently (C1-C6) alkyl optionally substituted withone or more of the same or different R⁸ groups or optionally R⁴ and R⁵together with the nitrogen atom to which they are bonded form acycloheteroalkyl ring;

R⁶ and R⁷ are independently hydrogen, alkyl optionally substituted withone or more of the same or different R⁸ groups, cycloalkyl optionallysubstituted with one or more of the same or different R⁸ groups,cycloheteroalkyl optionally substituted with one or more of the same ordifferent R⁸ groups, aryl optionally substituted with one or more of thesame or different R⁸ groups or heteroaryl optionally substituted withone or more of the same or different R⁸ groups; and

R⁸ is —F, —Cl, —Br, —I, —R⁶, —OR⁶, —SR⁶, —NR⁶R⁷, —CF₃, —CN, —C(O)R⁶,—C(O)OR⁶, —C(O)SR⁶, —C(O)NR⁶R⁷, or aryl which is optionally substitutedwith one or more —F, —Cl, —Br, —I, —R⁶, —OR⁶, —SR⁶, —NR⁶R⁷, —CF₃, —CN,—C(O)R⁶, —C(O)OR⁶, —C(O)SR⁶, or —C(O)NR⁶R⁷.

In another embodiment the invention provides a compound of formula Ia:

or a prodrug, salt, hydrate, solvate or N-oxide thereof wherein thecenter marked by * in the formula has the absolute configuration shown.

In another embodiment the invention provides a compound of formula IIb:

or a prodrug, salt, hydrate, solvate or N-oxide thereof wherein thecenter marked by * in the formula has the absolute configuration shown.

In another embodiment of the invention Z is:

In another embodiment of the invention Z is:

In another embodiment of the invention Z is:

In another embodiment of the invention R¹ is —OR⁶; and R⁶ is alkyloptionally substituted with one or more of the same or different R⁸groups.

In another embodiment of the invention R¹ is —OR⁶; and R⁶ is(C1-C6)alkyl.

In another embodiment of the invention R¹ is ethoxy, propoxy, or butoxy.

In another embodiment of the invention R² is the sidechain of a naturalamino acid.

In another embodiment of the invention R² is methyl, 3-guanidinopropyl,aminocarbonylmethyl, carboxymethyl, mercaptomethyl,2-carboxy-2-aminoethyldithiomethyl, 2-carboxyethyl,2-(aminocarbonyl)ethyl, imidazolylmethyl, 4-amino-3-hydroxybutyl,4-aminobutyl, 2-(methylthio)ethyl, hydroxymethyl, 1-hydroxyethyl,indolylmethyl, 4-hydroxybenzyl, isopropyl, 2-methylpropyl,1-methylpropyl, or benzyl.

In another embodiment of the invention R² is methyl, isopropyl,2-methylpropyl, 1-methylpropyl, or benzyl.

In another embodiment of the invention the center marked with * in acompound of formula IIa or IIb has an R absolute configuration.

In another embodiment of the invention the center marked with * in acompound of formula IIa or IIb has an S absolute configuration.

In another embodiment of the invention R⁴ and R⁵ are each independentlymethyl or ethyl.

In another embodiment of the invention R⁴ is hydrogen.

In another embodiment of the invention R⁴ and R⁵ are each hydrogen.

In another embodiment of the invention R⁴ and R⁵ together with thenitrogen atom to which they are bonded form a piperadino ring.

In another embodiment of the invention X is O.

In another embodiment of the invention n is 2, 3, or 4.

In another embodiment of the invention R² is (C3-C6) alkyl.

In another embodiment of the invention R² propyl, isopropyl, butyl,isobutyl, secbutyl, pentyl, isopentyl, secpentyl, or hexyl.

In another embodiment of the invention the compound of formula I is,

In another embodiment of the invention the compound of formula I is,

In another embodiment of the invention the compound of formula I is,

Transdermal Administration

The transdermal delivery of drugs has become a proven technology thatoffers a variety of significant clinical benefits over alternativeroutes of administration. Because transdermal drug delivery offerssustained and controlled release of the drug into the patient, itenables a steady blood-level to be maintained for an extended period oftime. This often results in reduced systemic side effects and,sometimes, improved efficacy over other dosage forms.

The efficiency of drug transport into or through the skin depends on anumber of factors such as the condition and type of skin, thephysicochemical characteristics of the permeant (the drug), otherchemicals present in the dosage form (e.g. penetration enhancers), andexternal conditions (e.g. temperature). The factors with perhaps thegreatest influence are the physicochemical characteristics of the drugmolecule. Based on the current understanding of the physicochemicalfeatures of molecules that are efficiently transported into and throughthe skin, it can be concluded that many of the compounds of formula I,formula Ia, and formula Ib possess favorable physicochemicalcharacteristics for transdermal penetration. These characteristicsinclude parameters such as LogP (the log of the octonol:water partitioncoefficient), aqueous solubility of the freebase form, and the molecularweight/molar volume. Accordingly, in one embodiment the inventionprovides compounds of formula I that possess physicochemicalcharacteristics that are favorable for transdermal penetration.

Methods of Synthesis

The compounds described herein may typically be obtained via the routeillustrated in Scheme 1. The compounds may also be prepared by otherprocedures known to those of skill in the art (See e.g., Green et al.,“Protective Groups in Organic Chemistry,” (Wiley, 2^(nd) ed. 1991);Harrison et al., “Compendium of Synthetic Organic Methods,” Vols. 1-8(John Wiley and Sons, 1971-1996); “Beilstein Handbook of OrganicChemistry,” Beilstein Institute of Organic Chemistry, Frankfurt,Germany; Feiser et al., “Reagents for Organic Synthesis,” Volumes 1-17,(Wiley Interscience); Trost et al., “Comprehensive Organic Synthesis,”(Pergamon Press, 1991); “Theilheimer's Synthetic Methods of OrganicChemistry,” Volumes 1-45, (Karger, 1991); March, “Advanced OrganicChemistry,” (Wiley Interscience), 1991; Larock “Comprehensive OrganicTransformations,” (VCH Publishers, 1989); Paquette, “Encyclopedia ofReagents for Organic Synthesis,” (John Wiley & Sons, 1995), Bodanzsky,“Principles of Peptide Synthesis,” (Springer Verlag, 1984); Bodanzsky,“Practice of Peptide Synthesis,” (Springer Verlag, 1984). Further,starting materials may be obtained from commercial sources or via wellestablished synthetic procedures, supra.

As illustrated in Scheme 1, where each R¹⁰ is independently hydrogen,—F, —Cl, —Br, —I, —R⁶, —OR⁶, —SR⁶, —NO₂ or —C(O)NR⁶R⁷, and X, R², R³,R⁴, R⁵ and n are as previously defined the acid chloride 1 is condensedwith amino alcohol or amino thiol 2 to provide compound 3 which can behydrogenated to provide aryl amine (I) if necessary. Those of skill inthe art will appreciate that reduction is only necessary if the compoundof Formula (I) is substituted with an amino group on the aromatic ring.Further, as known to the skilled artisan, a carboxylic acid can becondensed with amino alcohol or amino thiol 2 using conventionalprocedures known in the art. The amino alcohol and/or amino thiol 2 iseither commercially available or synthesized from commercially availablestarting materials using conventional chemistry known to those of skillin the art. Similarly, the benzoyl chloride is available fromcommercially available precursors using conventional methods.

Selection of appropriate protecting groups, reagents and reactionconditions for any of the steps in the above Scheme is well within theambit of those of skill in the art. Other methods for synthesis of thecompounds described herein will be readily apparent to the skilledartisan and may be used to provide the compounds described herein.Accordingly, the methods presented in the Schemes herein areillustrative rather than comprehensive.

Therapeutic Methods of Use

In general, the compounds disclosed herein or pharmaceuticalcompositions thereof may be used to induce and/or maintain localanesthesia and analgesia and are particularly useful for the prophylaxisand/or treatment of pain. As local anesthetics, the compounds disclosedherein or pharmaceutical compositions thereof are useful for regionalanesthesia, e.g., topical anesthesia, infiltration anesthesia,perisurgical tissue anesthesia, field block anesthesia, peripheral nerveblock anesthesia, epidural anesthesia, spinal anesthesia, bier blockanesthesia (local anesthetic injection into an extremity isolated by atourniquet) and combinations thereof. The compounds disclosed herein orpharmaceutical compositions thereof may also be used to relieve orprevent the pain associated with venipuncture, lumbar puncture,myringtomy, arterial cannulation, neuropathic pain, trauma and tissueischemia. The compounds disclosed herein or pharmaceutical compositionsthereof may be applied topically via patches, or other reservoirsystems, bandages or gauzes, creams, ointments or other transdermaldelivery systems to treat and/or prevent the pain associated with, forexamples, dermatoses, hemorrhoids and burns.

Pharmaceutical Compositions

The pharmaceutical compositions disclosed herein comprise a localanesthetic disclosed herein with a suitable amount of a pharmaceuticallyacceptable vehicle, so as to provide a form for proper administration toa subject.

Suitable pharmaceutical vehicles include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,cellulose, hydroxycellulose, lactose, methylcellulose,polyvinylpyrrolidone, microcrystalline cellulose, gum acacia, dried skimmilk, glycerol, propylene, glycol, water, ethanol, polyoxyethylenesorbitan derivatives and the like. The present pharmaceuticalcompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents. In addition, auxiliary,stabilizing, thickening, lubricating and coloring agents may be used.

Pharmaceutical compositions may be manufactured by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in any conventional manner using one ormore physiologically acceptable carriers, diluents, excipients orauxiliaries, which facilitate processing of compositions and compoundsdisclosed herein into preparations which can be used pharmaceutically.Proper formulation is dependent upon the route of administration chosen.

The present pharmaceutical compositions can take the form of solutions,suspensions, emulsions, powders, sustained-release formulations,aerosols, sprays, suspensions or any other form suitable for use knownto the skilled artisan. Other examples of suitable pharmaceuticalvehicles have been described in the art (see Remington's PharmaceuticalSciences, Philadelphia College of Pharmacy and Science, 19th Edition,1995).

In still other embodiments, the dosage form comprises compoundsdisclosed herein coated on a polymer substrate. The polymer can be anerodible, or a nonerodible polymer. The coated substrate may be foldedonto itself to provide a bilayer polymer drug dosage form. For example,compounds disclosed herein can be coated onto a polymer such as apolypeptide, collagen, gelatin, polyvinyl alcohol, polyorthoester,polyacetyl, or a polyorthocarbonate and the coated polymer folded ontoitself to provide a bilaminated dosage form. In operation, thebioerodible dosage form erodes at a controlled rate to dispense thecompounds over a sustained release period. Representative biodegradablepolymers comprise a member selected from the group consisting ofbiodegradable poly(amides), poly(amino acids), poly(esters), poly(lacticacid), poly(glycolic acid), poly(carbohydrate), poly(orthoester), poly(orthocarbonate), poly(acetyl), poly(anhydrides), biodegradablepoly(dihydropyrans), and poly(dioxinones) which are known in the art(Rosoff, Controlled Release of Drugs, Chap. 2, pp. 53-95 (1989); Helleret al., U.S. Pat. No. 3,811,444; Michaels, U.S. Pat. No. 3,962,414;Capozza, U.S. Pat. No. 4,066,747; Schmitt, U.S. Pat. No. 4,070,347; Choiet al., U.S. Pat. No. 4,079,038; Choi et al., U.S. Pat. No. 4,093,709).

In other embodiments, the dosage form comprises compounds disclosedherein loaded into a polymer that releases the drug(s) by diffusionthrough a polymer, or by flux through pores or by rupture of a polymermatrix. The drug delivery polymeric dosage form comprises aconcentration of 10 mg to 2500 mg homogenously contained in or on apolymer. The dosage form comprises at least one exposed surface at thebeginning of dose delivery. The non-exposed surface, when present, iscoated with a pharmaceutically acceptable material impermeable to thepassage of the drug(s). The dosage form may be manufactured byprocedures known in the art. An example of providing a dosage formcomprises blending a pharmaceutically acceptable carrier likepolyethylene glycol, with a known dose of compositions and/or compoundsdisclosed herein at an elevated temperature, (e.g., 37° C.), and addingit to a silastic medical grade elastomer with a cross-linking agent, forexample, octanoate, followed by casting in a mold. The step is repeatedfor each optional successive layer. The system is allowed to set forabout 1 hour, to provide the dosage form. Representative polymers formanufacturing the dosage form comprise a member selected from the groupconsisting of olefin, and vinyl polymers, addition polymers,condensation polymers, carbohydrate polymers, and silicone polymers asrepresented by polyethylene, polypropylene, polyvinyl acetate,polymethylacrylate, polyisobutylmethacrylate, poly alginate, polyamideand polysilicone. The polymers and procedures for manufacturing themhave been described in the art (Coleman et al., Polymers 1990, 31,1187-1231; Roerdink et al., Drug Carrier Systems 1989, 9, 57-10; Leonget al., Adv. Drug Delivery Rev. 1987, 1, 199-233; Roff et al., Handbookof Common Polymers 1971, CRC Press; Chien et al., U.S. Pat. No.3,992,518).

For topical administration a compound disclosed herein may be formulatedas emulsions, solutions, gels, ointments, creams, suspensions, jelliesetc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecal,infiltration or intraperitoneal injection, as well as those designed fortransdermal, transmucosal, oral or pulmonary administration. Systemicformulations may be made in combination with a further active agent thatimproves mucociliary clearance of airway mucus or reduces mucousviscosity. These active agents include but are not limited to sodiumchannel blockers, antibiotics, N-acetyl cysteine, homocysteine andphospholipids.

For injection, compounds disclosed herein may be formulated in aqueoussolutions, such as physiologically compatible buffers such as Hanks'solution, Ringer's solution, physiological saline buffer or in the formof an emulsion (as a water-in-oil or oil-in-water emulsion). In oneembodiment of the invention, the compound is formulated for injectionwith an organic acid buffer system (e.g. a (C1-C6) organic acid such ascitric, succinic, or acetic acid). The solution may also containformulatory agents such as suspending, stabilizing and/or dispersingagents. Alternatively, compounds disclosed herein may be in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

Vasoconstrictors (e.g., epinephrine or phenylepinephrine),corticosteroids (demaxthasone, cortisone, hydrocortisone, prednisone,beclamethasone, betamethasone, flunisolide, methylprednisone,prednisolone, triamcinolone, alcolmetasone, amcinonide, clobestal,fludrocortisone, difluorsone diacetate, fluocinolone acetonide,fluoromethalone, flurandrenolide, halcinonide, medrysone, etc.) and/orpermeability enhancers (e.g., sodium cholate, sodium glycocholate,sodium glycodeoxycholate, taurodeoxycholate, sodium deoxycholate, sodiumlithiocholate, chenocholate, chenodeoxycholate, ursocholate,ursodeoxycholate, hydrodeoxycholate, dehydrocholate, glycochenolate,taurochenocholate, taurochenodeoxycholate, etc.) can also be added tothe present pharmaceutical compositions.

Therapeutic/Prophylactic Administration and Doses

When used to maintain and/or induce anesthesia and/or analgesia, thecompounds disclosed herein and/or pharmaceutical compositions thereofmay be administered alone or in combination with other pharmaceuticalagents including compounds disclosed herein and/or pharmaceuticalcompositions thereof. The compounds disclosed herein may be administeredor applied per se or as pharmaceutical compositions. The specificpharmaceutical composition depends on the desired mode ofadministration, as is well known to the skilled artisan.

Compounds disclosed herein and/or pharmaceutical compositions thereofmay be administered to a subject by injection including intravenousinjection, continuous infusion, intramuscular injection, subcutaneousinjection, transdermally, intracerebrally, intravaginally, rectally,topically, particularly to the ears, nose, eyes, or skin or any otherconvenient method known to those of skill in the art. In someembodiments, compounds disclosed herein and/or pharmaceuticalcompositions thereof are delivered by infiltration methods such as, forexample, peripheral nerve blocks, serosal and neuraxial delivery, (e.g.,epidural, caudal, etc.)

Transdermal devices can also be used to deliver the compounds disclosedherein and/or pharmaceutical compositions thereof. In some embodiments,the transdermal device is a matrix type transdermal device (Miller etal., International Publication No. WO 2004/041324). In otherembodiments, the transdermal device is a multi-laminate transdermaldevice (Miller, United States Patent Application Publication No.2005/0037059).

The amount of compounds disclosed herein and/or pharmaceuticalcompositions thereof that will be effective in the treatment orprevention of pain in a patient will depend on the specific nature ofthe pain condition and can be determined by standard clinical techniquesknown in the art. The amount of compounds disclosed herein and/orpharmaceutical compositions thereof administered will, of course, bedependent on, among other factors, the subject being treated, the weightof the subject, the severity of the affliction, the manner ofadministration and the judgment of the prescribing physician.

Combination Therapy

In certain embodiments, compounds disclosed herein and/or pharmaceuticalcompositions thereof can be used in combination therapy with othertherapeutic agents, such as, for example, other local ester anestheticsand/or local amide anesthetics. The compounds disclosed herein and/orpharmaceutical compositions thereof and the therapeutic agent can actadditively or, more preferably, synergistically. In some embodiments,compounds disclosed herein and/or pharmaceutical compositions thereofare administered concurrently with the administration of anothertherapeutic agent. For example, compounds disclosed herein and/orpharmaceutical compositions thereof may be administered together withanother therapeutic agent. In other embodiments, compounds disclosedherein and/or pharmaceutical compositions thereof are administered prioror subsequent to administration of other therapeutic agents.

Screening

The quality and duration of local anesthetic block produced by a testcompound can be evaluated using the following Rat Sciatic Nerve Assay.

Rat Sciatic Nerve Assay

This assay enables evaluation of the efficacy of local anestheticmolecules via application of the compounds adjacent to the sciatic nervein the rat and measuring the anesthetic effects on response to painstimulus (toe pinch), motor function (postural hindlimb thrust) andproprioception (ability of the animal to balance) measured over time.

Each rat was tested for baseline hindpaw motor, proprioceptive, andsensory function and then injected with a test solution over the rightsciatic nerve. All tests were performed bilaterally starting on the sidethat was not injected.

Sciatic nerve injection: Rats were shaved over the right sciatic area.Rats were lightly anesthetized with 1.5% isoflurane until it waspossible to manipulate the hip joint. Test Solution(s) (200 uL) wereinjected proximal to the sciatic nerve using an insulin syringe directedbetween the greater trochanter and the ischial tuberosity.

Evaluations of anesthetic block included motor, sensory, andproprioceptive block assessed from injection time until all forms ofblock are absent.

Motor function was evaluated by measuring the extensor postural thrustof the bilateral hind limbs. The rat was held upright over a scale withthe hind limbs extended so that the body weight is supported by thedistal metatarsus and toes of one hindlimb. The extensor thrust wasmeasured as the gram force applied to the scale as the rat is pusheddown until the heel touches the balance. The pretreatment control valuewas considered to be 0% of the maximal possible effect (MPE). Thereduction in this force, representing reduced extensor musclecontraction induced by motor blockade, was calculated as percentage ofthe control force. A force <20 g was considered to be 100% of the MPE.

Proprioception was evaluated with a balancing test. A hopping responsewas evoked by lifting the rat into a vertical position with hindlimbsresting on the table and lifting one hindlimb at a time off the tabletop so that the animal's weight was resting on one hindlimb, then movingthe rat laterally until it hopped to the side to remain upright. Apredominantly motor impairment caused a prompt but weaker than normalresponse. Conversely, with a predominantly proprioceptive blockade,delayed hopping was followed by greater lateral hops to avoid fallingover or, in case of full blockade, no hopping at all. The proprioceptivedeficit was compared to the baseline response and graded as 4 (equal tobaseline or 0% MPE), 3 (slightly impaired), 2 (moderately impaired), 1(severely impaired) and 0 (complete or 100% MPE).

Nociceptive responses were measured with a forceps pinch test. Thewithdrawal response to forceps pinch applied to the distal phalanx ofdigit 5 was compared to the baseline response and graded as 4 (equal tobaseline or 0% MPE), 3 (slightly impaired), 2 (moderately impaired), 1(severely impaired), and 0 (absent or 100% MPE).

Representative compounds of the invention that were tested in the aboveRat Sciatic Nerve Assay were found to demonstrate clinically relevantlocal anesthetic activity. In all compounds tested, the efficacy (timeof complete conduction block) was superior to that demonstrated bylidocaine. In most cases, the efficacy was superior to that demonstratedby bupivacaine. Full clinical recovery was observed in all animalstested, demonstrating that the nerve blocks are fully reversible (i.e.the conduction block is likely not due to nerve damage induced by thecompounds).

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES Example 1 Synthesis of Compound 1

a. Synthesis of Intermediate B:

To a solution of dry THF (300 ml) was slowly charged lithium aluminumhydride (10.84 g, 0.151 mol) at 0° C. over 30 minutes. To this reactionmixture was charged, in portions, L-leucine (25.0 g, 0.213 mol) over aperiod of 45 minutes while maintaining the reaction mixture temperaturebetween 0-5° C. to control the vigorous evolution of hydrogen. Theresulting reaction mixture was then heated to reflux and maintained atreflux for 16 hours at which time it was cooled to 0-5° C., diluted withdiethyl ether (300 ml) and slowly quenched with DI water (12 ml). To thequenched solution was charged 15% w/v NaOH solution (12 ml) whichresulted in the precipitation of a white solid. The slurry was stirredat room temperature for 30 minutes and the white solid was removed byfiltration to give a clear organic filtrate which was dried with sodiumsulfate (q.s.). The sodium sulfate was removed by filtration and theorganic solution was concentrated under reduced pressure to afford B asa yellow liquid (18 g, 82%).

b. Synthesis of Intermediate C:

To a solution of absolute ethanol (200 ml) was charged B (10 g, 0.08mol) followed by dried potassium carbonate (58.9 g, 0.42 mol) and to theresulting slurry was charged, in drop wise fashion, 1,5-dibromopentane(23.35 ml, 0.17 mol). The reaction mixture was then heated to reflux andmaintained at reflux for 48 hours, then cooled to room temperature andfiltered through a celite bed. The organic layer was concentrated underreduced pressure to give an oil which was purified via silica gelchromatography, using petroleum ether:ethyl acetate as eluent. Thefractions containing Compound C were combined and the organic wasevaporated under reduced pressure to give Compound C as a yellow liquid(8.9 g, 56%).

c. Synthesis of Intermediate E:

To a solution of anhydrous ethanol (500 ml) was charged D (50 g, 0.27mol) and the reaction mixture was cooled to 0-5° C. at which timethionyl chloride (59.6 ml, 0.81 mol) was slowly added to keep thereaction mixture temperature <20° C. After complete thionyl chlorideaddition the reaction mixture was heated to reflux and maintained atreflux overnight. The reaction mixture was cooled to 20° C. and thenconcentrated to an oil by evaporation under reduced pressure. To theresidue was charged a mixture of water (200 ml) and ethyl acetate (200ml). The layers were separated and the aqueous was extracted withadditional ethyl acetate (2×200 ml). The combined organic layers werewashed with 10% sodium bicarbonate solution (200 ml), water (200 ml) andbrine (200 ml) and then dried over sodium sulfate, filtered andconcentrated under reduced pressure to give E as a yellow solid (51 g,89%).

d. Synthesis of Intermediate F:

To a solution of DMF (250 ml) was charged E (25 g, 0.11 mol) followed bypotassium carbonate (49.08 g, 0.35 mol) and the resulting slurry wascooled to 0-5° C. at which time n-butylbromide (16.6 ml, 0.15 mol) wascharged and the reaction mixture was stirred at room temperature for 24hours. To the reaction mixture was charged ethyl acetate (250 ml) andthe slurry was filtered through a bed of celite. The organic filtratewas washed with water (3×200 ml) and brine (200 ml) and then dried withsodium sulfate (q.s.) and concentrated under reduced pressure to give Fas a yellow solid (28 g, 88%).

e. Synthesis of Intermediate G:

To a solution of THF (150 ml) and water (150 ml) was charged F (14.98 g,0.062 mol) and to this reaction mixture was charged a solution oflithium hydroxide (7.5 g, 0.31 mol) in 50 ml of water, and the resultingmixture was stirred at room temperature overnight. The reaction mixturewas concentrated under reduced pressure to ⅓ its original volume and 1.5N HCl solution was added until the pH of the solution was <6. Thereaction mixture was extracted with ethyl acetate (2×200 ml) and thecombined organic layer was washed with water (100 ml) and then brine(100 ml), then dried with sodium sulfate (q.s.), concentrated underreduced pressure to give Compound G as a yellow solid (13 g, 97%).

f. Synthesis of Intermediate H:

To a solution of dichloromethane (30 ml) was charged Compound G (2.84 g,0.01 mol), C (2 g, 0.011 mol), Hunig's base (5.5 ml, 0.032 mol), EDCI(1.94 g, 0.016 mol) and HOBt (0.36 g, 0.0027 mol) and the reactionmixture was stirred at room temperature overnight. The reaction mixturewas then diluted with water (50 ml) and extracted with dichloromethane(100 ml). The combined organic layers were washed with 10% sodiumbicarbonate solution (50 ml), water (50 ml) and then brine (50 ml). Thesolution was then dried with sodium sulfate (q.s.), filtered andconcentrated under reduced pressure to give a brown liquid which waspurified by silica gel chromatography using 5% ethyl acetate/95%petroleum ether as eluent. The combined fractions were concentratedunder reduced pressure to give Compound H as a yellow liquid (2 g, 46%).

g. Synthesis of Compound 1 Hydrochloride Salt:

To a solution of methanol (50 ml) was charged Compound H (2 g, 0.004mol) followed by Pd—C (0.2 g, 10 mol %) and hydrogen gas was introducedand the reaction mixture was hydrogenated at 3.5 kg/cm2 for 2 hours. Thereaction mixture was then filtered over celite and the filtrate wasconcentrated under reduced pressure and the residue was purified usingsilica gel chromatography eluting with 1.5% methanol in chloroform. Thecombined fractions were evaporated under reduced pressure to giveCompound 1 free base as a brown liquid (0.238 g, 12%).

To a solution of chloroform (25 ml) was charged Compound 1 free base(0.238 g) and to this solution was charged HCl in diethylether (5 ml)and the reaction mixture was stirred at room temperature for 30 minutes.The solution was concentrated to dryness and diethyl ether wasre-charged and the resulting solid was collected and washed withdichloromethane and ethyl acetate to yield the hydrochloride salt ofCompound 1 as an off-white solid. HPLC purity (AUC): 95.0%, M+H+=377; 1HNMR (DMSO): δ (ppm)=0.9, m (9H); 1.4, m (3H); 1.7, m (8H); 2.0, m (2H);3.1, m (2H); 3.3, t (2H); 3.5, bs (1H); 4.0 t (2H); 4.5, m (2H); 6.3, d(1H); 6.4, s (1H); 7.7, d (1H); 10.8, bs (1H).

Example 2 Synthesis of Compound 2 Hydrochloride Salt

a. Synthesis of Intermediate B:

To a solution of dry THF (300 ml) was slowly charged lithium aluminumhydride (10.84 g, 0.151 mol) at 0° C. over 30 minutes. To this reactionmixture was charged, in portions, L-phenylalanine (25.0 g, 0.227 mol)over a period of 45 minutes while maintaining the reaction mixturetemperature between 0-5° C. to control the vigorous evolution ofhydrogen. The resulting reaction mixture was then heated to reflux andmaintained at reflux for 16 hours at which time it was cooled to 0-5°C., diluted with diethyl ether (300 ml) and slowly quenched with DIwater (12 ml). To the quenched solution was charged 15% w/v NaOHsolution (12 ml) which resulted in the precipitation of a white solid.The slurry was stirred at room temperature for 30 minutes and the whitesolid was removed by filtration to give a clear organic filtrate whichwas dried with sodium sulfate (q.s.). The sodium sulfate was removed byfiltration and the organic solution was concentrated under reducedpressure to afford intermediate B as yellow liquid (19 g, 84%).

b. Synthesis of Intermediate C:

To a solution of formic acid (7.48 ml, 0.19 mol) and formaldehyde (5.5ml, 0.19 mol) was charged intermediate B (10 g, 0.066 mol) and thereaction mixture was heated to reflux at 105° C. for 16 hours. Thereaction mixture was then cooled to room temperature and to the cooledsolution was charged 10% sodium hydroxide solution followed by ethylacetate (300 ml). The layers were separated and the organic layer waswashed with brine (100 ml), then dried with sodium sulfate, filtered andthe filtrate concentrated in vacuo to give intermediate C as a brownliquid (8 g, 67%).

c. Synthesis of Intermediate E:

To a solution of anhydrous ethanol (250 ml) was charged intermediate D(25 g, 0.137 mol) and the reaction mixture was cooled to 0-5 C at whichtime thionyl chloride (29.8 ml, 0.41 mol) was slowly added to keep thereaction mixture temperature <20 C. After complete thionyl chlorideaddition the reaction mixture was heated to reflux and maintained atreflux overnight. The reaction mixture was cooled to 20 C and thenconcentrated to an oil by evaporation under reduced pressure. To theresidue was charged a mixture of water (100 ml) and ethyl acetate (100ml). The layers were separated and the aqueous was extracted withadditional ethyl acetate (2×100 ml). The combined organic layers werewashed with 10% sodium bicarbonate solution (100 ml), water (100 ml) andbrine (100 ml) and then dried over sodium sulfate, filtered andconcentrated under reduced pressure to give intermediate E as a yellowsolid (27 g, 93%).

d. Synthesis of Intermediate F:

To a solution of DMF (250 ml) was charged intermediate E (27 g, 0.127mol) followed by potassium carbonate (53 g, 0.383 mol) and the reactionmixture was cooled to 0 C at which time n-propylbromide (12.8 ml, 0.140mol) was charged and the resulting slurry was stirred at roomtemperature for 24 hours. The reaction mixture was then diluted withethyl acetate (250 ml), filtered through a bed of celite and the cakewas washed with ethyl acetate (100 ml). The combined organic layers werewashed with water (3×200 ml) then brine (200 ml) and the organic layerwas dried with sodium sulfate and concentrated in vacuo to giveintermediate F as a yellow solid (25 g, 76%).

e. Synthesis of Intermediate G:

To a solution of THF (150 ml) and water (150 ml) was chargedintermediate F (21.0 g, 0.083 mol) and to this reaction mixture wascharged a solution of lithium hydroxide (10.0 g, 0.418 mol) in 50 ml ofwater, and the resulting mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressureto ⅓ its original volume and 1.5 N HCl solution was added until the pHof the solution was <6. The reaction mixture was extracted with ethylacetate (2×200 ml) and the combined organic layer was washed with water(100 ml) and then brine (100 ml), then dried with sodium sulfate (q.s.),concentrated under reduced pressure to give intermediate G as a yellowsolid (20 g, 83%).

f. Synthesis of Intermediate H:

To a solution of dichloromethane (30 ml) was charged intermediate G(2.76 g, 0.12 mol), C (2 g, 0.011 mol), Hunig's base (5.5 ml, 0.032mol), EDCI (1.94 g, 0.016 mol) and HOBt (0.36 g, 0.0027 mol) and thereaction mixture was stirred at room temperature overnight. The reactionmixture was then diluted with water (50 ml) and extracted withdichloromethane (100 ml). The combined organic layers were washed with10% sodium bicarbonate solution (50 ml), water (50 ml) and then brine(50 ml). The solution was then dried with sodium sulfate (q.s.),filtered and concentrated under reduced pressure to give a brown liquidwhich was purified by silica gel chromatography using 5% ethylacetate/95% petroleum ether as eluent. The combined fractions wereconcentrated under reduced pressure to give intermediate H as a yellowliquid (1.3 g, 30%).

g. Synthesis of Compound 2 Hydrochloride Salt (I):

To a solution of methanol (50 ml) was charged intermediate H (1.3 g,0.0034 mol) followed by Pd—C (0.13 g, 10 mol %) and hydrogen gas wasintroduced and the reaction mixture was hydrogenated at 3.5 kg/cm2 for 2hours. The reaction mixture was then filtered over celite and thefiltrate was concentrated under reduced pressure and the residue waspurified using silica gel chromatography eluting with 1.5% methanol inchloroform. The combined fractions were evaporated under reducedpressure to give Compound 2 free base as a brown liquid (0.44 g, 34%).

To a solution of chloroform (25 ml) was charged Compound 2 free base(0.44 g) and to this solution was charged HCl in diethylether (5 ml) andthe reaction mixture was stirred at room temperature for 30 minutes. Thesolution was concentrated to dryness and diethyl ether was re-chargedand the resulting solid was collected and washed with dichloromethaneand ethyl acetate to yield the hydrochloride salt of Compound 2 as anoff-white solid. HPLC purity (AUC): 98.5%; M+H+=357; 1H NMR (DMSO): δ(ppm)=1.0, t (3H); 1.9, m (2H); 2.5, s (6H); 2.8, m (1H); 3.0, m (1H);3.1, m (1H); 4.0, t (2H); 4.4, m (2H); 6.8, d (1H); 7.2, m (5H); 7.4, s(1H); 7.5, s (1H).

Example 3 Synthesis of Compound 3 Hydrochloride Salt

a. Synthesis of Intermediate B:

To a solution of dry THF (250 ml) was slowly charged lithium aluminumhydride (10.84 g, 0.151 mol) at 0 C over 30 minutes. To this reactionmixture was charged, in portions, L-leucine (25.0 g, 0.227 mol) over aperiod of 45 minutes while maintaining the reaction mixture temperaturebetween 0-5 C to control the vigorous evolution of hydrogen. Theresulting reaction mixture was then heated to reflux and maintained atreflux for 16 hours at which time it was cooled to 0-5 C, diluted withdiethyl ether (300 ml) and slowly quenched with DI water (12 ml). To thequenched solution was charged 15% w/v NaOH solution (12 ml) whichresulted in the precipitation of a white solid. The slurry was stirredat room temperature for 30 minutes and the white solid was removed byfiltration to give a clear organic filtrate which was dried with sodiumsulfate (q.s.). The sodium sulfate was removed by filtration and theorganic solution was concentrated under reduced pressure to affordintermediate B as a yellow liquid (20 g, 90%).

b. Synthesis of Intermediate C:

To a solution of formic acid (9.6 ml, 0.25 mol) and formaldehyde (7.1ml, 0.25 mol) was charged intermediate B (10 g, 0.08 mol) and thereaction mixture was heated to reflux at 105 C for 16 hours. Thereaction mixture was then cooled to room temperature and to the cooledsolution was charged 10% sodium hydroxide solution followed by ethylacetate (300 ml). The layers were separated and the organic layer waswashed with brine (100 ml), then dried with sodium sulfate, filtered andthe filtrate concentrated in vacuo to give intermediate C as a brownliquid (8.2 g, 66%).

c. Synthesis of Intermediate E:

To a solution of anhydrous ethanol (500 ml) was charged intermediate D(50 g, 0.27 mol) and the reaction mixture was cooled to 0-5 C at whichtime thionyl chloride (59.6 ml, 0.81 mol) was slowly added to keep thereaction mixture temperature <20 C. After complete thionyl chlorideaddition the reaction mixture was heated to reflux and maintained atreflux overnight. The reaction mixture was cooled to 20 C and thenconcentrated to an oil by evaporation under reduced pressure. To theresidue was charged a mixture of water (200 ml) and ethyl acetate (200ml). The layers were separated and the aqueous was extracted withadditional ethyl acetate (2×200 ml). The combined organic layers werewashed with 10% sodium bicarbonate solution (200 ml), water (200 ml) andbrine (200 ml) and then dried over sodium sulfate, filtered andconcentrated under reduced pressure to give intermediate E as a yellowsolid (51 g, 89%).

e. Synthesis of Intermediate F:

To a solution of DMF (250 ml) was charged intermediate E (25.5 g, 0.12mol) followed by potassium carbonate (49.65 g, 0.36 mol) and thereaction mixture was cooled to 0 C at which time n-propylbromide (16.5ml, 0.18 mol) was charged and the resulting slurry was stirred at roomtemperature for 24 hours. The reaction mixture was then diluted withethyl acetate (250 ml), filtered through a bed of celite and the cakewas washed with ethyl acetate (100 ml). The combined organic layers werewashed with water (3×200 ml) then brine (200 ml) and the organic layerwas dried with sodium sulfate and concentrated in vacuo to giveintermediate F as a yellow solid (28 g, 92%).

f. Synthesis of Intermediate G:

To a solution of THF (150 ml) and water (150 ml) was chargedintermediate F (30 g, 0.118 mol) and to this reaction mixture wascharged a solution of lithium hydroxide (14.2 g, 0.59 mol) in 50 ml ofwater, and the resulting mixture was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressureto ⅓ its original volume and 1.5 N HCl solution was added until the pHof the solution was <6. The reaction mixture was extracted with ethylacetate (2×200 ml) and the combined organic layer was washed with water(100 ml) and then brine (100 ml), then dried with sodium sulfate (q.s.),concentrated under reduced pressure to give intermediate G as a yellowsolid (22 g, 82%).

g. Synthesis of Intermediate H:

To a solution of dichloromethane (30 ml) was charged intermediate G(3.41 g, 0.12 mol), C (2 g, 0.013 mol), Hunig's base (7 ml, 0.041 mol),EDCI (3.97 g, 0.021 mol) and HOBt (0.38 g, 0.025 mol) and the reactionmixture was stirred at room temperature overnight. The reaction mixturewas then diluted with water (50 ml) and extracted with dichloromethane(100 ml). The combined organic layers were washed with 10% sodiumbicarbonate solution (50 ml), water (50 ml) and then brine (50 ml). Thesolution was then dried with sodium sulfate (q.s.), filtered andconcentrated under reduced pressure to give a brown liquid which waspurified by silica gel chromatography using 5% ethyl acetate/95%petroleum ether as eluent. The combined fractions were concentratedunder reduced pressure to give intermediate H as a yellow liquid (1.2 g,25%).

h. Synthesis of Compound 3 Hydrochloride Salt:

To a solution of methanol (50 ml) was charged intermediate H (1.2 g,0.003 mol) followed by Pd—C (0.12 g, 10 mol %) and hydrogen gas wasintroduced and the reaction mixture was hydrogenated at 3.5 kg/cm2 for 2hours. The reaction mixture was then filtered over celite and thefiltrate was concentrated under reduced pressure and the residue waspurified using silica gel chromatography eluting with 1.5% methanol inchloroform. The combined fractions were evaporated under reducedpressure to give Compound 3 free base as a brown liquid (0.37 g, 30%).

To a solution of chloroform (25 ml) was charged Compound 3 free base(0.44 g) and to this solution was charged HCl in diethylether (5 ml) andthe reaction mixture was stirred at room temperature for 30 minutes. Thesolution was concentrated to dryness and diethyl ether was re-chargedand the resulting solid was collected and washed with dichloromethaneand ethyl acetate to yield the hydrochloride salt of Compound 3 as anoff-white solid. HPLC purity (AUC): 91.4%; M+H+=323; 1H NMR (DMSO): δ(ppm)=0.9, m (6H); 1.0, t (3H); 1.8, m (5H); 2.7, s (3H); 2.8, s (3H);3.7, bs (1H); 4.0, t (2H); 4.5, m (2H); 6.4, d (1H); 6.5, s (1H); 7.8, d(1H).

Example 4 General Synthesis of Representative Compounds

Other representative compounds of formula I can be prepared using thefollowing general synthetic scheme.

a. Synthesis of Substituted Amino Alcohol Coupling Pieces:

To a solution of a polar non protic solvent such as THF is charged ahydride source, such as lithium aluminum hydride (0.5 to 2.0equivalents) followed by an amino acid, such as L-Leucine, L-isoleucine,L-phenyalanine (A) and the mixture is refluxed for 12-24 hours untilreduction is complete. This mixture is cooled to 0-10 C, diluted with apolar non protic solvent such as diethyl ether and is quenched withwater and basified with a sodium hydroxide solution, such as 15% sodiumhydroxide solution. The resulting solid is washed with this polar nonprotic solvent, dried with magnesium or sodium sulfate and concentratedin vacuo to afford the product (B) as a liquid.

b. Synthesis of Piperidinyl Containing Amino Alcohol Intermediates

To a solution of compound B is charged an alcoholic solvent such asethanol, followed by potassium or sodium carbonate followed by additionof 1,5-dibromopentane and the reaction mixture is heated to reflux for48-72 hours, then cooled to room temperature and filtered through a bedof celite. Concentration of the organic layer in vacuo gives an oilwhich is purified by silica gel chromatography. The fractions containingpure product are combined and the solvent removed in vacuo to providethe piperidinyl compounds.

c. Synthesis of Dimethyl or Dimethyl Containing Amino AlcoholIntermediates—Dimethyl Compound Procedure Provided Below.

To a solution of formic acid and formaldehyde is charged compound B andthe reaction mixture is heated to reflux for 16-24 hours and then iscooled to room temperature at which time a sodium hydroxide solution ischarged followed by an organic solvent such as ethyl acetate. Afterwashing of the organic layer with brine and drying with sodium ormagnesium sulfate and filtration, the filtrate is concentrated in vacuoto give C.

d. Synthesis of Common Intermediate G:

To a solution of a protic polar solvent, such as ethanol, is charged2-hydroxy-4-nitrobenzoic acid followed by a chlorinating agent such asthionyl chloride. After reflux for 8-16 hours the reaction mixture isconcentrated and extracted with an organic solvent such as ethylacetate, washed with sodium carbonate solution, water and brine and theorganic evaporated in vacuo to afford the product as a yellow solid.

e. To a solution of a polar non-protic solvent such as DMF is chargedCompound E and potassium carbonate followed by an alkyl bromide (such asn-ethyl, n-propyl or n-butylbromide) and the reaction mixture is stirredat room temperature for 16-30 hours. The reaction mixture is dilutedwith an organic solvent, such as ethyl acetate, and is washed with waterand brine and concentrated in vacuo to afford the product as a yellowsolid.f. To a solution of a polar non-protic organic solvent such as THF andwater is charged Compound F and an alkyl hydroxide, such as lithiumhydroxide, and the solution is stirred at room temperature for 8-16hours. The reaction mixture is concentrated, acidified with an HClsolution, such as 1.5 M HCl solution and is extracted with an organicsolvent such as ethyl acetate. The organic solution is washed with waterand brine and dried over magnesium or sodium sulfate and concentrated invacuo to afford the product as an off-white solid.g.

To a solution of a non-polar organic solvent is charged G, an aminoalcohol, EDCI, HOBt and an amine base, (e.g. Hunig's base), and thereaction mixture is allowed to stir overnight at room temperature. Thereaction mixture is then diluted with water, extracted with a non-polarorganic solvent and washed with bicarbonate solution, brine and driedwith magnesium or sodium sulfate. Purification by silica gelchromatography gives the product H as an oil.

h. To a solution of an alcoholic solvent, preferably methanol, ischarged H, a Pd—C catalyst and hydrogen gas is introduced and thereaction mixture stirred for several hours. The reaction mixture isfiltered over celite, the filtrate is evaporated under reduced pressureand the residue is purified by silica gel chromatography to give thefree base of compound I. The free base is dissolved in a non-polarorganic solvent and HCl in a non-polar organic solvent is introduced.The solution is concentrated to dryness and an organic solvent, such asdiethyl ether, is charged resulting in precipitation of a solid which iscollected to afford compound I as its hydrochloride salt.

Example 5 Synthesis of Representative Compounds 4, 5, and 6

To a 500 ml flask was charged A, 4-nitro-2-R₁-benzoic acid [where R₁ ispropoxy or butoxy] (10 g, 0.044 mol), followed by methanol (100 ml) andto the resulting solution was charged 10% Pd—C (1 g) and the flask waspressurized with 4 kg/cm² of hydrogen and the reaction mixture wasallowed to stir at room temperature overnight. After reaction completionwas confirmed by TLC analysis the reaction mixture was filtered overcelite and the filtrate was concentrated in vacuo to give compound B asa brown solid (7.99 grams, 91% yield).

To a 500 ml round bottom flask was charged B (8.1 g, 0.042 mol) followedby concentrated sulfuric acid (162 ml) and water (162 ml) and thereaction mixture was heated to 80° C. at which time a pre-made solutionof sodium nitrite (3.9 g, 0.062 mol) was charged in portions. Afterstirring at this temperature for 3-4 hours, reaction completion wasconfirmed by TLC analysis, the mixture was cooled to 20° C. and thenpoured over ice (q.s.) followed by extraction with ethyl acetate. Theorganic was washed with water and then brine and dried with sodiumsulfate (q.s.) and then concentrated in vacuo to give a solid which waspurified by silica gel chromatography (9:1 chloroform:methanol) to givecompound C as a red solid (7.5 g, 92%).

Into a 250 ml round bottom flask was charged compound C (7.4 g, 0.038mol) followed by ethanol (70 ml) and water (7 ml), benzyl bromide (7.05g, 0.042 mol) and potassium hydroxide (4.23 g, 0.076 mol) and themixture was heated to reflux for 18 hours until reaction completion wasconfirmed by TLC analysis. The reaction mixture was cooled to roomtemperature and the ethanol was removed in vacuo to ⅕ the originalvolume. The solution was neutralized with 1.5 N HCl and then extractedwith ethyl acetate. The organic was washed with water and then brine anddried with sodium sulfate then concentrated in vacuo to give crudecompound D. Compound D was purified by silica gel chromatography using5:1 petroleum ethyl/ethyl acetate to give compound D as a pale yellowsolid (3.0 g, 27% yield).

Into a 100 ml round bottom flask was charged dichloromethane (25 ml)followed by compound D (1.1 g, 0.0038 mol), compound E[N,N-dimethylleucinol, N,N diethylleucinol or N,N diethylphenylalaminol](0.95 eq), Hunig's base (1.36 g, 0.0105 mol), EDC (1.0 g, 0.0053 mol),and HOBt (0.1 g, 0.0009 mol) and the reaction mixture was stirredovernight at room temperature until TLC analysis confirmed reactioncompletion. The reaction mixture was concentrated in vacuo, ethylacetate was charged to the residue and the resulting solution was washedwith water and brine, dried with sodium sulfate and concentrated invacuo to give crude compound F. The crude material was purified bysilica gel chromatography (7:3 petroleum ether/ethyl acetate) to givecompound F as a yellow liquid (0.15 g, 10%).

Into a 50 ml round bottom flask was charged methanol (10 ml) followed byPd—C (25 mg) and the mixture was hydrogenated overnight at roomtemperature under 4 kg/cm² of hydrogen pressure until TLC analysisshowed reaction completion. The reaction mixture was filtered overcelite and the filtrated was concentrated under reduced pressure to givecrude compound 4, which was purified by silica gel:chromatography (9:1chloroform/methanol) to provide a yellow liquid. Compounds 5 and 6 wereprepared using a similar procedure.

Example 6 Synthesis of Representative Compounds 7 and 8

Compounds 7 and 8 can also be prepared using the following syntheticscheme wherein R₁ is propyl or butyl and R₂ is N,N-dimethylisoleucinolor N,N-diethylisoleucinol.

It will be apparent to those skilled in the art that many modifications,both to materials and methods, may be practiced without departing fromthe scope of this disclosure. Accordingly, the present embodiments areto be considered as illustrative and not restrictive, and the inventionis not to be limited to the details given herein, but may be modifiedwithin the scope and equivalents of the allowed claims.

All publications and patents cited herein are incorporated by referencein their entirety.

1-2. (canceled)
 3. A compound of formula IIa or IIb:

or a prodrug, salt, hydrate, solvent or N-oxide thereof, wherein: Z is agroup of the following formula:

each R¹ is independently hydrogen, —F, —Cl, —Br, —I, —R⁶, —OR⁶, —SR⁶,—NR⁶R⁷ or —C(O)NR⁶R⁷; p is an integer from 1 to 3; X is —O— or —S—; R²is the sidechain of an amino acid; or is selected from methyl,3-guanidinopropyl, aminocarbonylmethyl, carboxymethyl, mercaptomethyl,2-carboxy-2-aminoethyldithiomethyl, 2-carboxyethyl,2-(aminocarbonyl)ethyl, imidazolylmethyl, 4-amino-3-hydroxybutyl,4-aminobutyl, 2-(methylthio)ethyl, hydroxymethyl, 1-hydroxyethyl,indolylmethyl, 4-hydroxybenzyl, isopropyl, 2-methylpropyl,1-methylpropyl, and benzyl; or is (C3-C6) alkyl; R⁴ and R⁵ areindependently H, (C1-C6) alkyl optionally substituted with one or moreof the same or different R⁸ groups or optionally R⁴ and R⁵ together withthe nitrogen atom to which they are bonded form a cycloheteroalkyl ring;R⁶ and R⁷ are independently hydrogen, alkyl, cycloalkyl,cycloheteroalkyl, aryl or heteroaryl; and R⁸ is —F, —Cl, —Br, —I, —R⁶,—OR⁶, —SR⁶, —NR⁶R⁷, —CF₃, —CN, —C(O)R⁶, —C(O)OR⁶, —C(O)SR⁶, —C(O)NR⁶R⁷,or aryl which is optionally substituted with one or more —F, —Cl, —Br,—I, —R⁶, —OR⁶, —SR⁶, —NR⁶R⁷, —CF₃, —CN, —C(O)R⁶, —C(O)OR⁶, —C(O)SR⁶, or—C(O)NR⁶R⁷; wherein the center marked by * in the formula has theabsolute configuration shown provided that the compound is not:


4. (canceled)
 5. The compound of claim 3 wherein Z is:

6-7. (canceled)
 8. The compound of claim 3 wherein Z is:

9-13. (canceled)
 14. The compound of claim 3 wherein R² is the sidechainof a natural amino acid.
 15. The compound of claim 3 wherein R² ismethyl, isopropyl, 2-methylpropyl, 1-methylpropyl, or benzyl. 16-17.(canceled)
 18. The compound of claim 3 wherein R⁴ and R⁵ are eachindependently methyl or ethyl.
 19. The compound of claim 3 wherein R⁴and R⁵ together with the nitrogen atom to which they are bonded form apiperadino ring.
 20. The compound of claim 3 wherein X is O.
 21. Acompound having the structure:


22. A compound having the structure:

23-27. (canceled)
 28. The compound of claim 3 wherein R² is (C3-C6)alkyl.
 29. The compound of claim 3 wherein R² is propyl, isopropyl,butyl, isobutyl, secbutyl, pentyl, isopentyl, secpentyl, or hexyl.
 30. Apharmaceutical composition comprising a compound of claim 3 and apharmaceutically acceptable vehicle.
 31. (canceled)
 32. A method ofinducing or maintaining local anesthesia in a patient comprisingadministering to the patient a compound of claim
 3. 33. A method ofinducing or maintaining local anesthesia in a patient comprisingadministering to the patient in need thereof the pharmaceuticalcomposition of claim
 30. 34. A method of treating or preventing pain ina patient comprising administering to the patient in need thereof acompound of claim
 3. 35-37. (canceled)
 38. The compound of claim 3,wherein Z is:

wherein R¹ is ethoxy, propoxy or butoxy.
 39. The compound of claim 3,wherein R² is selected from methyl, 3-guanidinopropyl,aminocarbonylmethyl, carboxymethyl, mercaptomethyl,2-carboxy-2-aminoethyldithiomethyl, 2-carboxyethyl,2-(aminocarbonyl)ethyl, imidazolylmethyl, 4-amino-3-hydroxybutyl,4-aminobutyl, 2-(methylthio)ethyl, hydroxymethyl, 1-hydroxyethyl,indolylmethyl, 4-hydroxybenzyl, isopropyl, 2-methylpropyl,1-methylpropyl, and benzyl.
 40. A compound of formula IIa:

or a prodrug, salt, hydrate, solvent or N-oxide thereof, wherein: Z is agroup of the following formula:

each R¹ is independently hydrogen, —F, —Cl, —I, —R⁶, —OR⁶, —SR⁶, —NR⁶R⁷or —C(O)NR⁶R⁷; p is an integer from 1 to 3; X is —O— or —S—; R² is thesidechain of an amino acid; or is selected from methyl,3-guanidinopropyl, aminocarbonylmethyl, carboxymethyl, mercaptomethyl,2-carboxy-2-aminoethyldithiomethyl, 2-carboxyethyl,2-(aminocarbonyl)ethyl, imidazolylmethyl, 4-amino-3-hydroxybutyl,4-aminobutyl, 2-(methylthio)ethyl, hydroxymethyl, 1-hydroxyethyl,indolylmethyl, 4-hydroxybenzyl, isopropyl, 2-methylpropyl,1-methylpropyl, and benzyl; or is (C3-C6) alkyl; R⁴ and R⁵ areindependently H, (C1-C6) alkyl optionally substituted with one or moreof the same or different R⁸ groups or optionally R⁴ and R⁵ together withthe nitrogen atom to which they are bonded form a cycloheteroalkyl ring;R⁶ and R⁷ are independently hydrogen, alkyl, cycloalkyl,cycloheteroalkyl, aryl or heteroaryl; and R⁸ is —F, —Cl, —Br, —I, —R⁶,—OR⁶, —SR⁶, —NR⁶R⁷, —CF₃, —CN, —C(O)R⁶, —C(O)OR⁶, —C(O)SR⁶, —C(O)NR⁶R⁷,or aryl which is optionally substituted with one or more —F, —Cl, —Br,—I, —R⁶, —OR⁶, —SR⁶, —NR⁶R⁷, —CF₃, —CN, —C(O)R⁶, —C(O)OR⁶, —C(O)SR⁶, or—C(O)NR⁶R⁷; wherein the center marked by * in the formula has theabsolute configuration shown.
 41. A compound of formula IIb:

or a prodrug, salt, hydrate, solvent or N-oxide thereof, wherein: Z is agroup of the following formula:

each R¹ is independently hydrogen, —F, —Cl, —I, —R⁶, —OR⁶, —SR⁶, —NR⁶R⁷or —C(O)NR⁶R⁷; p is an integer from 1 to 3; X is —O— or —S—; R² is thesidechain of an amino acid; or is selected from methyl,3-guanidinopropyl, aminocarbonylmethyl, carboxymethyl, mercaptomethyl,2-carboxy-2-aminoethyldithiomethyl, 2-carboxyethyl,2-(aminocarbonyl)ethyl, imidazolylmethyl, 4-amino-3-hydroxybutyl,4-aminobutyl, 2-(methylthio)ethyl, hydroxymethyl, 1-hydroxyethyl,indolylmethyl, 4-hydroxybenzyl, isopropyl, 2-methylpropyl,1-methylpropyl, and benzyl; or is (C3-C6) alkyl; R⁴ and R⁵ areindependently H, (C1-C6) alkyl optionally substituted with one or moreof the same or different R⁸ groups or optionally R⁴ and R⁵ together withthe nitrogen atom to which they are bonded form a cycloheteroalkyl ring;R⁶ and R⁷ are independently hydrogen, alkyl, cycloalkyl,cycloheteroalkyl, aryl or heteroaryl; and R⁸ is —F, —Cl, —Br, —I, —R⁶,—OR⁶, —SR⁶, —NR⁶R⁷, —CF₃, —CN, —C(O)R⁶, —C(O)OR⁶, —C(O)SR⁶, —C(O)NR⁶R⁷,or aryl which is optionally substituted with one or more —F, —Cl, —Br,—I, —R⁶, —OR⁶, —SR⁶, —NR⁶R⁷, —CF₃, —CN, —C(O)R⁶, —C(O)OR⁶, —C(O)SR⁶, or—C(O)NR⁶R⁷; wherein the center marked by * in the formula has theabsolute configuration shown.
 42. A compound of formula IIa:

or a prodrug, salt, hydrate, solvent or N-oxide thereof, wherein: Z is agroup of the following formula:

R¹ is —OR⁶, wherein R⁶ is C1-C6 alkyl; X is —O—; R² is methyl,isopropyl, 2-methylpropyl, 1-methylpropyl, or benzyl; R⁴ and R⁵ areindependently H, (C1-C6) alkyl or R⁴ and R⁵ together with the nitrogenatom to which they are bonded form a cycloheteroalkyl ring; wherein thecenter marked by * in the formula has the absolute configuration shown.